Compounds and methods for the treatment of isocitrate dehydrogenase related diseases

ABSTRACT

The invention relates to compounds of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/037,761, filed on Sep. 26, 2013, which is a continuation ofInternational Application No. PCT/US2012/031245, which designated theUnited States and was filed on Mar. 29, 2012, published in English,which claims the benefit of U.S. Provisional Application No. 61/469,054,filed on Mar. 29, 2011. The entire teachings of the above applicationsare incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under Grant No. CA148399awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND

Cancer genomics is revealing comprehensively somatic mutations that mayconstitute the root cause of disease. These findings suggest novelmechanisms for cancer initiation and progression, and new ways we mighttreat cancer in the future. Recently, a genome-wide sequencing studyidentified mutations in the metabolic enzyme IDH1 in samples frompatients with glioblastoma multiforms, which are among the most lethalcancers with survival of only months after their diagnosis. (Parsons D.W. et al., Science 321, 1807-1812, 2008). Subsequent analyses revealedthat mutations in IDH1 are common (70%-80%) in grade II, III gliomas andsecondary glioblastomas and that patients lacking IDH1 mutations oftenharbor mutations in IDH2, which shares 70% identity with IDH1. (Yan H.et al., N Engl J Med 360, 765-773, 2009; Bleeker F. E. et al., Hum Mutat30, 7-11, 2009; Balss J. et al., Acta Neuropathol 116, 597-602, 2008).More recently, IDH1/2 mutations have been observed in acute myeloidleukemia (AML) and rare cases have been reported in other cancers. (WardP. S. et al., Cancer Cell 17, 225-234, 2010; Exp. Med. 207, 339-344,2010; Mardis E. R. et al., N Engl J Med 361, 1058-1066, 2009). Notably,all mutations in IDH1/2 are heterozygous and the majority of them affecta particular codon (R132 in IDH1 and the analogous codon, R172, in IDH2)suggesting the gene may contribute to carcinogenesis as an oncogenerather than a tumor suppressor through a gain of function.

IDH1/2 are NADP+-dependent isocitrate dehydrogenases that normallymediate oxidative decarboxylation of isocitrate to α-ketoglutarate(α-KG) via the conversion of NADP+ to NADPH. Mutations in IDH1/2 appearto have two functional consequences for the enzymes' activities: i) adecreased ability to convert isocitrate to α-KG; and ii) a new abilityto reduce α-KG to (R)-2-hydroxyglutarate (2-HG) using NADPH (Ward etal., supra; Dang, L. et al., Nature 462, 739-744, 2009). Indeed 2-HGlevels are elevated >50-fold in samples from patients withIDH1/2-mutations. This observation has motivated study of 2-HG as adisease biomarker, as well as deeper study into the molecular mechanismby which this putative ‘oncometabolite’ might contribute to disease.Indeed, 2-HG could interfere with a wide range of processes, such asthose regulated by α-KG-dependent, iron-dependent dioxygenases; theseprocesses include the response to hypoxic stress (mediated by EglNprolyl hydroxylases), DNA modification (mediated by TET2, a5-methylcytosine hydroxylase), and histone methylation (mediated byJmjC-containing demethylases), among others (Figueroa M. E. et al.,Cancer Cell, 18, 553-567, 2010; Christensen, B. C. et al., J. Natl.Cancer Inst. 103, 2, 143-53, 2011; Zhao, S. et al., Science, 324,261-265, 2009; Xu, W. et al., Cancer Cell, 19, 17-30, 2011). Thus, thedevelopment of small molecules that inhibit the 2-HG-generating activityof IDH1/2 mutants in cells is important in cancer cell biology and drugdevelopment.

Point mutations IDH1 and IDH2 occur early in the pathogenesis ofgliomas. Reitman reports that the study of 200 metabolites in humanoligodendroglioma (HOG) cells to determine the effects of expression ofIDH1 and IDH2 mutants showed that the levels of amino acids, glutathionemetabolites, choline derivatives, and tricarboxylic acid (TCA) cycleintermediates were altered in mutant IDH1- and IDH2-expressing cells.(Reitman Z. J. et al., Proc. Natl. Acad. Sci. 2011, 108(8) 3270-3275).Furthermore, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide inbrain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-foldreduced in cells expressing IDH2 mutants.

Hartmann et al., (US 20100291590) discloses a method for the diagnosisof a brain tumor using the presence/absence of a particular IDH1mutation as a marker. Vogelstein et al. (WO 2010/028099) discloses thatmutations in IDH1 and IDH2 are related to astrocytomas,oligodendrogliomas and glioblastomas. Dang et al., (WO 2010/105243)discloses methods for the treatment of isocitrate dehydrogenase relatedproliferative disorders.

Glioblastoma is the most frequent and most malignant human brain tumor.The prognosis remains very poor, with most patients dying within 1 yearafter diagnosis. (Ohgaki et al. American Journal of Pathology, 170(5),2007, 1445-1453). There exists a need to develop effective treatmentsagainst proliferative disorders including glioblastoma and acute myeloidleukemia. Thus, there exists a need to focus on developing compoundsthat inhibit mutated IDH1/2 with selectivity over wild-type IDH1/2 withthe goal of targeting cancer cells selectively over normal cell. Thatsaid, there is also a need for advancing compounds that target bothmutant and wild-type IDH1/2 since cancer cells which harbor mutant IDHalleles are dependent on the wild-type allele for proliferation,suggesting inhibition of wild-type IDH may also prove valuable fortreating cancer (Ward P. S. et al., Cancer Cell 17, 225-234, 2010).

SUMMARY OF THE INVENTION

The invention relates to compounds of Formula I or a pharmaceuticallyacceptable salt, ester or prodrug thereof and their use in themanufacture of a medicament, in particular, for the treatment of a cellproliferative disease:

-   -   each n and m is independently 0, 1, 2 or 3;    -   each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;    -   X₁ is —C(O)N(R_(A))—, —C(S)N(R_(A))—, or —S(O)₂N(R_(A))—;        -   wherein R_(A) is hydrogen, aliphatic, substituted aliphatic,            heteroaryl, substituted heteroaryl, aryl or substituted            aryl;    -   X₂ is —S— —O—, —S(O)₂—, —C(R₂₀)(R₂₁)— or —N(R_(B))—;        -   wherein R_(B) is hydrogen, aliphatic, substituted aliphatic,            heteroaryl, substituted heteroaryl, aryl or substituted            aryl;    -   each R₁ and R₂ is independently hydrogen, halogen, aliphatic,        substituted aliphatic, aryl or substituted aryl;    -   each R₁₀ is independently absent, hydrogen, halogen, —OR₂₀,        —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)OR₂₀, —C(O)R₂₀,        —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino,        substituted alkylamino, dialkylamino, substituted dialkylamino,        substituted or unsubstituted alkylthio, substituted or        unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,        aryl or substituted aryl; alternatively two of R₁₀ groups        together with the atoms to which they are attached and any        intervening atoms may form an additional optionally substituted,        3, 4, 5, 6 or 7 membered ring;        -   wherein each R₂₀ and R₂₁ is independently hydrogen, halogen,            aliphatic, substituted aliphatic, aryl or substituted aryl;    -   each R₁₁ is independently absent, hydrogen, halogen, —OR₂₀,        —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)OR₂₀, —C(O)R₂₀,        —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino,        substituted alkylamino, dialkylamino, substituted dialkylamino,        substituted or unsubstituted alkylthio, substituted or        unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,        aryl or substituted aryl; alternatively two of R₁₁ groups        together with the atoms to which they are attached and any        intervening atoms may form an additional optionally substituted,        3, 4, 5, 6 or 7 membered ring; and,    -   Cy1 is an optionally substituted aryl or optionally substituted        heteroaryl.

The invention further relates to the use of a compound of Formula I inthe manufacture of a medicament. The invention further relates to theuse of a compound of Formula I for the treatment of a cell proliferativedisease and the use of a compound of Formula I in the manufacture of amedicament for the treatment of a cell proliferative disease.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1(A): Diagram of the assay principle for the IDH1-R132H enzymaticassay.

FIG. 1(B): Optimization of resazurin concentration to give the highestsignal-to-background ratio.

FIG. 1(C): Reaction time course of the IDH1-R132H enzyme assay inbuffers with magnesium or manganese.

FIG. 1 (D): Km of α-Ketoglutarate with 20 μM or 5 μM of NADPH.

FIG. 1 (E): The effect of DMSO on the IDH1-R132H assay.

FIG. 1 (F): Reaction time course of the IDH1-R132H assay.

FIG. 1 (G): Concentration-response of the IDH1-R132H enzyme. The assaywas linear at 8 μm/ml.

FIG. 2(A-B): Both (A) consumption of NADPH by IDH1-R132H, and (B)production of NADPH by wild-type IDH1 can be monitored by measuringabsorbance at 340 nm.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of Formula I or a pharmaceuticallyacceptable salt, ester or prodrug thereof, and their use in themanufacture of a medicament, in particular, for the treatment of a cellproliferative disease:

-   -   each n and m is independently 0, 1, 2 or 3;    -   each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;    -   X₁ is —C(O)N(R_(A))—, —C(S)N(R_(A))—, or —S(O)₂N(R_(A))—;        -   wherein R_(A) is hydrogen, aliphatic, substituted aliphatic,            heteroaryl, substituted heteroaryl, aryl or substituted            aryl;    -   X₂ is —S— —O—, —S(O)₂— —C(R₂₀)(R₂₁)— or —N(R_(B))—;        -   wherein R_(B) is hydrogen, aliphatic, substituted aliphatic,            heteroaryl, substituted heteroaryl, aryl or substituted            aryl;    -   each R₁ and R₂ is independently hydrogen, halogen, aliphatic,        substituted aliphatic, aryl or substituted aryl;    -   each R₁₀ is independently absent, hydrogen, halogen, —OR₂₀,        —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)OR₂₀, —C(O)R₂₀,        —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino,        substituted alkylamino, dialkylamino, substituted dialkylamino,        substituted or unsubstituted alkylthio, substituted or        unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,        aryl or substituted aryl; alternatively two of R₁₀ groups        together with the atoms to which they are attached and any        intervening atoms may form an additional optionally substituted,        3, 4, 5, 6 or 7 membered ring;        -   wherein each R₂₀ and R₂₁ is independently hydrogen, halogen,            aliphatic, substituted aliphatic, aryl or substituted aryl;    -   each R₁₁ is independently absent, hydrogen, halogen, —OR₂₀,        —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)OR₂₀, —C(O)R₂₀,        —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino,        substituted alkylamino, dialkylamino, substituted dialkylamino,        substituted or unsubstituted alkylthio, substituted or        unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic,        aryl or substituted aryl; alternatively two of R₁₁ groups        together with the atoms to which they are attached and any        intervening atoms may form an additional optionally substituted,        3, 4, 5, 6 or 7 membered ring; and,    -   Cy1 is an optionally substituted aryl or optionally substituted        heteroaryl.

In one embodiment, the invention relates to a compound of Formula II-IIIor a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein, n, p, q, X₂, Cy1, R₁, R₂, R₁₀, and R₁₁ are as defined above;andR₃ is hydrogen, halogen, aliphatic, substituted aliphatic, aryl orsubstituted aryl.

In a preferred embodiment, the invention relates to a compound ofFormula IIIA:

wherein R₃a is selected from alkyl, aryl, alkyl substituted with aryl,straight chain or branched C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl,C₁-C₁₀ alkoxy, alkoxyC₁-C₁₀alkoxy, C₁-C₁₀alkylamino,alkoxyC₁-C₁₀alkylamino, C₁-C₁₀ alkylcarbonylamino, C₁-C₁₀alkylaminocarbonyl, aryloxyC₁-C₁₀ alkoxy, aryloxyC₁-C₁₀alkylamino,aryloxyC₁-C₁₀ alkylamino carbonyl, C₁-C₁₀-alkylaminoalkylaminocarbonyl,C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀ alkoxy, alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylamino C₁-C₁₀ alkoxy, alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl, piperazinoalkylaryl,heteroarylC₁-C₁₀ alkyl, heteroarylC₁-C₁₀alkenyl, heteroarylC₁-C₁₀alkynyl, heteroarylC₁-C₁₀ alkylamino, heteroarylC₁-C₁₀alkoxy,heteroaryloxyC₁-C₁₀alkyl, heteroaryloxyC₁-C₁₀ alkenyl,heteroaryloxyC₂-C₁₀ alkynyl, heteroaryloxyC₁-C₁₀alkylamino,heteroaryloxyC₁-C₁₀ alkoxy.

In one embodiment, the invention relates to a compound of Formula IV-Vor a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein p, q, X₂, R₁, R₂, R₃, R₁₀, and R₁₁ are as defined above.

In a preferred embodiment, the invention relates to a compound ofFormula V wherein R₃ is R₃a, and R₃a is as defined above.

In a preferred embodiment, the invention relates to a compound ofFormula I, II, III, IV or V wherein, R₁ is an optionally substitutedalkyl. In a preferred embodiment, R₁ is an optionally substituted C₁-C₆alkyl, more preferably selected from methyl, ethyl, propyl, cyclopropyl,isopropyl, n-butyl, tert-butyl, cyclobutyl, n-pentyl, neopentyl,cyclopentyl, n-hex yl and cyclohexyl.

In one embodiment, the invention relates to a compound of Formula I-IIIwherein Cy1 is selected from Table A:

TABLE A

wherein

represents a single or double bond;each R₁₂ is independently absent, hydrogen, —C(O)R₂₀, —C(O)OR₂₀,—C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, substituted orunsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl,aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl orsubstituted heteroaryl;d is 0, 1 or 2;alternatively, two R₁₁ and R₁₂ groups may form an optionally substituted3, 4, 5, 6, or 7 membered ring.

In one embodiment the invention relates to a compound of Formula I-V andR₁₁ is selected from Table B:

TABLE B

wherein, t is 0, 1, 2, 3, 4, 5, 6 or 7;Cy2 is an optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted heterocyclyl, optionallysubstituted aryl or optionally substituted heteroaryl;each R₁₃, R₁₄ and R₁₅ is independently absent, hydrogen, halogen, —OR₂₀,—SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)R₂₀, —C(O)OR₂₀,—C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy, alkylamino, substitutedalkylamino, dialkylamino, substituted dialkylamino, substituted orunsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl,aliphatic, substituted aliphatic, aryl or substituted aryl;alternatively two R₁₃ groups together with the atoms to which they areattached and any intervening atoms may form an additional optionallysubstituted, 3, 4, 5, 6 or 7 membered ring; and,each R₁₆, R₁₇ and R₁₈ is independently hydrogen, halogen, aliphatic,substituted aliphatic, aryl substituted aryl, heteroaryl or substitutedheteroaryl;alternatively two of R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ groups togetherwith the atoms to which they are attached, and any intervening atoms mayform an optionally substituted 3, 4, 5, 6 or 7 membered ring.

In one embodiment the invention relates to a compound of Formula I-Vwherein R₂ is selected from Table C:

TABLE C

wherein u and w is independently 0, 1, 2, 3, 4, 5 or 6; and,Cy3 is optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted heterocyclyl, optionallysubstituted aryl or optionally substituted heteroaryl.

In a preferred embodiment, u is 1. In a preferred embodiment, w is 1. Ina preferred embodiment, Cy3 is an optionally substituted aryl, morepreferably an optionally substituted heteroaryl.

In a preferred embodiment, the invention relates to a compound ofFormula I-III wherein Cy1 is selected from Table A, q is 1 and R₁₁ isselected from Table B, and R₂ is selected from Table C.

In one embodiment, the invention relates to a compound of Formula II-IIIwherein n is 0, X₂ is O, and Cy1 is an optionally substituted aryl. In apreferred embodiment, Cy1 is an optionally substituted phenyl ring. In apreferred embodiment Cy1 is a phenyl group and R₁₁ is selected fromTable B, and R₂ is selected from Table C.

In one embodiment the invention relates to a compound of Formula I-Vwherein R₃ is selected from Table D:

TABLE D

In a preferred embodiment, the invention relates to a compound ofFormula I-V wherein Cy1 is selected from Table A, q is 1 and R₁₁ isselected from Table B, R₂ is selected from Table C, and R₃ is selectedfrom Table D. In a more preferred embodiment, R₄ is an optionallysubstituted alkyl group, preferably a C1-C8 alkyl.

In one embodiment the invention relates to a compound of Formula IIIwherein R₃ is selected from Table E:

TABLE E

wherein, t, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ are as defined above;r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;R₃₀ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl orsubstituted heteroaryl;each R₃₁, and R₃₂ is independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl or substituted heteroaryl; and,R₃₃ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃,—C(O)OR₂₀, —C(O)R₂₀, —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy,alkylamino, substituted alkylamino, dialkylamino, substituteddialkylamino, substituted or unsubstituted alkylthio, substituted orunsubstituted alkylsulfonyl wherein R₂₀ and R₂₁ are as defined above.

In a preferred embodiment, R₃₀ is C₁-C₁₀ alkyl, C₁-C₁₀alkylaryl, orC₁-C₁₀alkylarylalkoxy.

In a preferred embodiment, R₁₆ is aryl, substituted aryl, heteroaryl orsubstituted heteroaryl.

In a preferred embodiment, a compound of Formula I is selected fromTable 1:

TABLE 1 1

(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 2

1-(4-fluorophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 3

(4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-8-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 4

N-(((4R,5R)-8-(cyclohexylethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-4-yl)acetamide 5

1-cyclohexyl-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 6

N-(((4R,5R)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 7

N-((2S,3S)-5-((R)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin-10-yl)benzo[d]thiazole-2-carboxamide 8

(4R,5R)-8-(cyclopropylethynyl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 9

(4R,5S)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-4-ylmethyl)amino)methyl)-8-(p-tolyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 10

(4S,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-8-(pent-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 11

N-(((4R,5S)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 12

(4R,5S)-8-(cyclohex-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 13

(4S,5S)-8-(cyclopent-1-en-1-yl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-4-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 14

N-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)cyclohexanecarboxamide 15

N-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-2-(((4-methoxybenzyl)(methyl)amino)methyl)-3-methyl-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)cyclohexanecarboxamide 16

(4S,5S)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-4-ylmethyl)amino)methyl)-8-(o-tolyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 17

(2S,3S)-5-((R)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyrimidin-5-ylmethyl)amino)methyl)-8-((E)-styryl)-4,5-dihydro-2H-pyrido[2,3-b][1,5]oxazocin-6(3H)-one 18

4-(((((4R,5R)-8-(3-cyclopentylprop-1-yn-1-yl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)(methyl)amino)methyl)benzoic acid 19

N-(((4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-8-(3-methylbut-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methylnicotinamide 20

N-(((4R,5R)-8-(cyclohex-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 21

N-(((4S,5S)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 22

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-isopropylurea 23

1-(4-bromophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 24

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(4-methoxyphenyl)urea 25

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(pyridin-3-yl)urea 26

1-cyclopentyl-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 27

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(2-morpholinopyridin-4-yl)urea 28

1-ethyl-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 29

1-(4-chlorophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 30

1-(cyclohexylmethyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 31

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-phenylurea 32

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(naphthalen-1-yl)urea 33

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(4-(trifluoromethyl)phenyl)urea34

1-(benzo[d][1,3]dioxo1-5-yl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 35

1-(3,5-dimethylisoxazol-4-yl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 36

N-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)cyclopropanecarboxamide 37

N-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)isonicotinamide 38

1-(2-fluorophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 39

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea40

1-(4-cyanophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 41

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(3-(pyrimidin-2-yl)phenyl)urea 42

1-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-(2-(piperidin-1-yl)phenyl)urea 43

1-(benzofuran-5-yl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 44

1-cyclohexyl-3-((2R,3R)-2-((((3-fluoropyridin-4-yl)methyl)(methyl)amino)methyl)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 45

1-((2R,3R)-2-((((3-chloropyridin-4-yl)methyl)(methyl)amino)methyl)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-cyclohexylurea 46

1-cyclohexyl-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyrimidin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 47

1-cyclohexyl-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(quinolin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 48

1-((2R,3R)-2-((((1H-imidazol-2-yl)methyl)(methyl)amino)methyl)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)-3-cyclohexylurea 49

1-cyclohexyl-3-((2R,3R)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-5-((S)-1-(2-(pyrrolidin-1-yl)ethoxy)propan-2-yl)-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 50

1-cyclohexyl-3-((2R,3R)-5-((S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 51

1-cyclohexyl-3-((2R,3R)-5-((S)-1-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 52

1-cyclohexyl-3-((2R,3R)-5-isopropyl-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea 53

1-cyclohexyl-3-((2R,3R)-5-((S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-3-methyl-2-((methyl((3-methylpyridin-4-yl)methyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea

The invention further relates to a process for preparing compounds ofFormula I-V. Scheme 1 shows a general methodology for the synthesis ofmedium-sized ring scaffolds from a common linear intermediate used forthe synthesis of final compounds.

R_(c) and R_(D) are each independently hydrogen, halogen, —OR₂₀, —SR₂₀,—NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁, acyl,alkoxy, substituted alkoxy, alkylamino, substituted alkylamino,dialkylamino, substituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic,substituted aliphatic, aryl or substituted aryl.

For this synthetic route (Scheme 1), intermediates and medium-sized ringscaffolds were synthesized using the procedures similar to Marcaurelle,L. A. et al., J. Am. Chem. Soc. 2010, 132, 16962-16976.

The compounds shown in the synthetic route (Scheme 2), intermediates andfinal compounds were synthesized using a procedure similar to thatreported in Marcaurelle, L. A. et al., J. Am. Chem. Soc. 2010, 132,16962-16976.

Abbreviations

Abbreviations which may appear in the synthetic schemes and examplesare:

Ac for acetyl;

Alloc for allyloxycarbonyl;

Boc for tert-butoxycarbonyl;

DCM for dichloromethane;

DMF for dimethyl formamide;

DMSO for dimethyl sulfoxide;

EtOAc for ethyl acetate;

iPr for isopropyl;

IPA for isopropyl alcohol;

MeOH for methanol;

TEA for triethylamine; and

TFA for trifluoroacetic acid.

The invention further provides methods for the prevention or treatmentof diseases or conditions involving aberrant proliferation,differentiation or survival of cells. The invention relates to thetreatment of cell proliferative disease, such as cancer, by theadministration of a compound of Formula I-V to a patient in needthereof.

In a preferred embodiment, the cancer is selected from glioma, acutemyeloid leukemia (AML), Burkitt's leukemia/lymphoma (B-ALL), melanomaand prostate carcinoma. In a preferred embodiment, the disease isselected from Grade I, II, III or IV glioma. In a preferred embodiment,the disease is selected from astrocytomas, oligodendrogliomas,ependymomas and glioblastoma multiforme (GBM).

The invention further relates to a method of treating a disease relatedto a defect in isocitrate dehydrogenase comprising the step ofadministering a compound according to any of the above claims to apatient in need thereof, in particular wherein said defect in isocitratedehydrogenase is a somatic mutation at codon 132 isocitratedehydrogenase (IDH1) or at codon 172 in isocitrate dehydrogenase 2(IDH2). The invention further relates to the treatment of Grade I, II,III and IV glioma. The glioma can be selected from astrocytomas,oligodendrogliomas, ependymomas and glioblastoma multiforme (GBM).

The invention further provides methods for the prevention or treatmentof diseases related to defects in isocitrate dehydrogenase (IDH1 orIDH2) by administration of a compound of Formula I-III. The inventionrelates to diseases associated with somatic mutations at codon 132isocitrate dehydrogenase (IDH1), and at codon 172 and 140 in isocitratedehydrogenase 2 (IDH2). The invention further relates to the treatmentof patients with one more mutations at codons 132 of IDH1 and 172 or 140of IDH2. The invention further relates to the treatment of diseasesassociated with mutations to IDH1 selected from R132H, R132C, R132S,R132L, and R132G. The invention further relates to treatment of diseasesassociated with mutations to 1DH2 selected from R172M, R172G, R172K andR140Q. In one embodiment, the disease associated with the abovementioned mutations is a cell proliferative disease, in particularcancer. In a preferred embodiment, the cell proliferative disease isselected from glioma, acute myeloid leukemia (AML), Burkitt'sleukemia/lymphoma (B-ALL), melanoma and prostate carcinoma. In apreferred embodiment, the disease is selected from Grade I, II, III orIV glioma. In a preferred embodiment, the disease is selected fromastrocytomas, oligodendrogliomas, ependymomas and glioblastomamultiforme (GBM).

In one embodiment, the invention relates to the inhibition of IDH1/2 byadministration of a compound of Formula I-V. In one embodiment, thecompound of Formula I-V inhibits the wild type IDH1. In one embodiment,the compound of Formula I-V inhibits wild type IDH2.

In one embodiment, the invention relates to the administration of acompound of Formula I-V in patient that exhibit abnormal2-hydroxyglutarate (2-HG) production. In one embodiment, the patientexhibit an increase in 2-HG production of more than about 20 fold, ormore than about 40 fold or more than about 50 fold or more than about100 fold or more than about 200 fold compared to normal tissue. Theincreased 2-HG production can be localized to tumor tissue. In oneembodiment, the abnormal 2-HG production is due to a mutation in 1DH1 or1DH2.

In one embodiment, the invention relates to a method of treating adisease related to a defect in isocitrate dehydrogenase comprising thestep of administering a compound according to a compound of Formula I-Vto a patient in need thereof, wherein the compound selectively inhibitmutant of IDH1 or a mutant of IDH2 over the respective wild type IDH. Inone embodiment, a compound of Formula I-V selectively inhibits a mutantof IDH1 over the wild type IDH1. In one embodiment, the ratio ofinhibitory activity against an IDH1 mutant over the wild type IDH1 isabout 2 to about 1000, preferably about 5 to about 500, preferably about10 to about 100, preferably about 25 to about 100. In one embodiment,the mutation to IDH1 is selected from R132H, R132C, R132S, R132L, andR132G. In one embodiment, a compound of Formula I-V selectively inhibitsa mutant of IDH2 over the wild type IDH2. In one embodiment, the ratioof inhibitory activity against an IDH2 mutant over the wild type IDH2 isabout 2 to about 1000, preferably about 5 to about 500, preferably about10 to about 100, preferably about 25 to about 100. In one embodiment,the mutation to IDH2 is selected from R172M, R172G, R172K and R140Q.

The invention further relates to the use of a compound of Formula I inthe manufacture of a medicament. The invention further relates to theuse of a compound of Formula I for the treatment of a cell proliferativedisease and the use of a compound of Formula I in the manufacture of amedicament for the treatment of a cell proliferative disease.

In one embodiment, the invention relates to the administration of acompound of Formula I-V in combination with a second pharmacologicalagent for the treatment of a cell proliferative disease. In oneembodiment, the second pharmacological agent is selected from vatalanib(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034,gefitinib, erlotinib, HKI-272, CI-1033 or GW-2016, iressa (ZD-1839),tarceva (OSI-774), PKI-166, EKB-569, herceptin, BAY-43-9006,BAY-57-9006, atrasentan, rituximab, cetuximab, bevacizumab, bivatuzumabmertansine, IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin,imatinib or dasatinib, VEGFtrap, melphalan, cyclophosphamide, anoxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin,tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU),lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa,chlorambucil, mechlorethamine, an ethyleneimine compound, analkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomaldoxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine,dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol,mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin,propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosoureaor a derivative thereof, cytarabine, 5-fluorouracile (5-FU), pemetrexed,tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine,mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin,hydroxyurea, or folic acid, a phleomycin, a bleomycin or a derivative orsalt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or aderivative thereof, a rifamycin, an actinomycin, adramycin, acamptothecin such as irinotecan (camptosar) or topotecan, an amsacrineor analogue thereof, a tricyclic carboxamide, a histonedeacetylaseinhibitor such as SAHA, MD-275, trichostatin A, CBHA, LAQ824, orvalproic acid, an anti-cancer drug from plants such as paclitaxel(taxol), docetaxel or taxotere, navelbine, vinblastin, vincristin,vindesine, vinorelbine, colchicine or a derivative thereof, maytansine,an ansamitocin or rhizoxin, phomopsin, dolastatin, an epipodophyllotoxinor a derivative of podophyllotoxin, etoposide, teniposide, a steganacin,combretastatin, amphetinile, procarbazine, bortezomib, asparaginase,pegylated asparaginase (pegaspargase), a thymidine-phosphorylaseinhibitor, a gestagen, an estrogen, estramustine (T-66), megestrol, ananti-androgen, flutamide, casodex, anandron or cyproterone acetate,aminogluthetimide, anastrozole, formestan, exemestane, letrozole,leuprorelin, buserelin, goserelin, triptorelin, an anti-estrogen,tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene,zindoxifene, an estrogen receptor antagonist such as fulvestrant, aderivative of 17.beta.-estradiol, ICI 164,384, ICI 182,780,aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, aLH-RH antagonist, leuprolide, a steroid, prednisone, prednisolone,methylprednisolone, dexamethasone, budenoside, fluocortolone,triamcinolone, interferon.beta., IL-10, IL-12, an anti-TNF.alpha.antibody, etanercept, TNF-.alpha. (tasonermin), thalidomide and its R-and S-enantiomers and its derivatives, revimid (CC-5013), a leukotrienantagonist, mitomycin C, BMY-42355, AZQ or EO-9, a 2-nitroimidazolemisonidazole, NLP-1 or NLA-1, a nitroacridine, a nitroquinoline, anitropyrazoloacridine, RSU-1069, RB-6145, CB-1954, nitromin, an anti-CD3or anti-CD25 antibody, a tolerance induction agent, minodronic acid andits derivatives (YM-529, Ono-5920, YH-529), zoledronic acid monohydrate,ibandronate sodium hydrate, clodronate disodium, metronidazole,misonidazole, benznidazole, nimorazole, RSU-1069, SR-4233,bromodeoxyuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, abenzoporphyrin derivative, a pheophorbide derivative, merocyanin 540(MC-540), tin etioporpurin, an anti-template, an anti-sense RNA or DNA,oblimersen, a non-steroidal inflammatory drug, acetylsalicyclic acid,mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen,ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid,fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone,diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac,acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid,diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide,meloxicam, celecoxib, rofecoxib, a pharmaceutically acceptable salt of anon-steroidal inflammatory drug, a cytotoxic antibiotic, an antibodytargeting the surface molecules of cancer cells, apolizumab, 1D09C3,TIMP-1, TIMP-2, Zinc, an inhibitor of oncogenes, P53, R.sup.b,heterocyclic complexes of lanthanides, PUVA, an inhibitor of thetranscription factor complex ESX/DRIP130/Sur-2, an inhibitor of HER-2expression, the heat shock protein HSP90 modulator geldanamycin and itsderivative 17-allylaminogeldanamycin or 17-AAG, therapeutic agentselected from IM-842, tetrathiomolybdate, squalamine, combrestatin A4,TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab,mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukindiftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,pipobroman, plicamycin, tamoxifen and testolactone.

In one embodiment, the invention further provides for the use of one ormore compounds of the invention in the manufacture of a medicament forhalting or decreasing diseases involving aberrant proliferation,differentiation, or survival of cells. In one embodiment, the inventionrelates to a method of treating cancer in a subject in need of treatmentcomprising administering to said subject a therapeutically effectiveamount of a compound of the invention.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”). Otherpreferred alkyl groups comprise at about 1 to about 8 carbon atoms(“C₁-C₈”) such as about 1 to about 6 carbon atoms (“C₁-C₆”), or such asabout 1 to about 3 carbon atoms (“C₁-C₃”). Examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl and n-hexylradicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkenyl radicals are “lower alkenyl” radicals having two to about tencarbon atoms (“C₂-C₁₀”) such as ethenyl, allyl, propenyl, butenyl and4-methylbutenyl. Preferred lower alkenyl radicals include 2 to about 6carbon atoms (“C₂-C₆”). The terms “alkenyl”, and “lower alkenyl”,embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkynyl radicals are “lower alkynyl” radicals having two to about tencarbon atoms such as propargyl, 1-propynyl, 2-propynyl, 1-butyne,2-butynyl and 1-pentynyl. Preferred lower alkynyl radicals include 2 toabout 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means an aromatic systemcontaining one, two or three rings wherein such rings may be attachedtogether in a pendent manner or may be fused. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanefuranyl, quinazolinyl, pyridyl and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound”, “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genito urinary cancers (e.g., prostate, bladder, renal, uterine,ovarian, testicular), lung cancer (e.g., small-cell and non-small cell),breast cancer, pancreatic cancer, melanoma and other skin cancers,stomach cancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the invention, thepresent invention provides for the use of one or more compounds of theinvention in the manufacture of a medicament for the treatment ofcancer.

In one embodiment, the present invention includes the use of one or morecompounds of the invention in the manufacture of a medicament thatprevents further aberrant proliferation, differentiation, or survival ofcells. For example, compounds of the invention may be useful inpreventing tumors from increasing in size or from reaching a metastaticstate. The subject compounds may be administered to halt the progressionor advancement of cancer. In addition, the instant invention includesuse of the subject compounds to prevent a recurrence of cancer.

This invention further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

“Combination therapy” includes the administration of the subjectcompounds in further combination with other biologically activeingredients (such as, but not limited to, a second and differentantineoplastic agent) and non-drug therapies (such as, but not limitedto, surgery or radiation treatment). For instance, the compounds of theinvention can be used in combination with other pharmaceutically activecompounds, preferably compounds that are able to enhance the effect ofthe compounds of the invention. The compounds of the invention can beadministered simultaneously (as a single preparation or separatepreparation) or sequentially to the other drug therapy. In general, acombination therapy envisions administration of two or more drugs duringa single cycle or course of therapy.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid, gel or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta-(β) and gamma-(γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics is knownin the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter etal., U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 byMontgomery).

EXAMPLES Example 1: Synthesis of(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine1,1-dioxide

Scaffold Loading:

To a flame-dried flask containing silicon-functionalized Lanterns wasadded a freshly prepared solution of TfOH in anhydrous DCM (9.0 equiv, 5g of TfOH/100 mL of DCM) was added. Each flask was shaken at RT for 10min at which time the Lanterns had turned bright orange. The deep redTfOH solution was removed via cannula and anhydrous 2,6-lutidine (12.0equiv relative to Si) was added. Once the Lantern color had changed fromorange to white,(9H-fluoren-9-yl)methyl(((4R,5R)-8-bromo-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)(methyl)carbamate,the scaffold, (1.2 equiv. relative to Si) was added as a solution inanhydrous DCM (0.4 mL/Lantern) and the reaction mixture was shaken for48 h overnight. The loading mixture was removed and set aside (torecover any unreacted alcohol) and the Lanterns were washed with thefollowing solvents for 30 min intervals: DCM, THF, 3:1 THF/IPA, 3:1THF/H₂O, DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. The Lanterns were thendried on a lyophilizer overnight and carried on to the next step.

Fmoc Removal:

To a flask containing Lanterns was added a solution of 20% piperidine inDMF (0.8 mL/Lantern). After shaking at rt for 30 min, the piperidinesolution was removed and the Lanterns were washed with the followingsolvents for 30 min intervals: DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM.QC analysis of an aliquot cleaved from the lantern shows no remainingstarting material. The Lanterns were then dried on a lyophilizerovernight and carried on to the next step.

N-Capping/Aldehydes:

To a flask containing Lanterns was added DMF with 2% AcOH (0.800mL/Lantern) followed by 4-pyridinecarboxaldehyde (20 equiv). Thereaction mixture was shaken at rt for 1 hr then sodiumtriacetoxyborohydride (20 equiv) was added and shaking was continued.After 3 days the reaction mixture was removed and the Lanterns werewashed with the following solvents for 30 min intervals: DMF, 3:1THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of an aliquot cleaved fromthe lantern shows no remaining starting material. The Lanterns were thendried on a lyophilizer overnight and carried on to the next step.

Cross-Coupling/Suzuki:

To each flask containing Lanterns was added ethanol (0.800 mL/Lantern)followed by cyclopent-1-en-1-ylboronic acid (20 equiv), triethylamine(40 equiv) and Pd(PPh₃)₂Cl₂ (1 equiv). The resulting mixture wasdegassed with a stream of N₂ before shaking at 60° C. After 4 days, thereaction mixture was removed and the Lanterns were washed with followingsolvents for 30 min intervals: DCM, DMF, NaCN solution (0.1M) in 1:1THF/H₂O, DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of analiquot cleaved from the lantern shows no remaining starting material.

Cleavage Protocol:

To a 96-well plate containing Lanterns was added a 15% solution ofHF/pyridine in stabilized THF (350 μL/Lantern). After 2 h the cleavagesolution was quenched with TMSOMe (700 μL/Lantern) and the contents ofeach well were transferred to a pre-weighed 2-mL vial. The Lanterns werewashed with an additional 200 μL of stabilized THF (or THF/MeOH) and thesolution was transferred to the 2-mL vial. The samples were concentratedon a GENEVAC® solvent evaporation system overnight without heating toafford the title compound(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine1,1-dioxide (7.5 mg, 86% yield). LCMS RT 0.81 min, observed[M+1]⁺485.23, calculated [M+1]⁺485.245). Loading masses for each alcoholwas determined on a FLEXIWEIGH® system.

Example 2: Synthesis of1-(4-fluorophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea

Scaffold Loading:

To a flame-dried flask containing silicon-functionalized Lanterns wasadded a freshly prepared solution of TfOH in anhydrous DCM (9.0 equiv, 5g of TfOH/100 mL of DCM) was added. Each flask was shaken at RT for 10min at which time the Lanterns had turned bright orange. The deep redTfOH solution was removed via cannula and anhydrous 2,6-lutidine (12.0equiv relative to Si) was added. Once the Lantern color had changed fromorange to white,allyl(((2R,3R)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-2-yl)methyl)(methyl)carbamate,the scaffold (1.2 equiv. relative to Si) was added as a solution inanhydrous DCM (0.4 mL/Lantern) and the reaction mixture was shaken for48 h overnight. The loading mixture was removed and set aside (torecover any unreacted alcohol) and the Lanterns were washed with thefollowing solvents for 30 min intervals: DCM, THF, 3:1 THF/IPA, 3:1THF/H₂O, DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. The Lanterns were thendried on a lyophilizer overnight and carried on to the next step.

Fmoc Removal:

To a flask containing Lanterns was added a solution of 20% piperidine inDMF (0.8 mL/Lantern). After shaking at rt for 30 min, the piperidinesolution was removed and the Lanterns were washed with the followingsolvents for 30 min intervals: DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM.QC analysis of an aliquot cleaved from the lantern shows no remainingstarting material. The Lanterns were then dried on a lyophilizerovernight and carried on to the next step.

N-Capping/Isocyanates:

To a flask containing Lanterns was added DCM (0.8 mL/Lantern) followedby 4-fluorophenyl isocyanate (15 equiv). The Lanterns were shaken at rtovernight and then washed with the following solvents for 30 minintervals: DCM, DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis ofan aliquot cleaved from the lantern shows no remaining starting material(a stereoisomer is shown). The Lanterns were then dried on a lyophilizerovernight and carried on to the next step.

Alloc Removal:

To the reaction vessel containing Lanterns, THF (0.8 mL/Lantern) wasadded, followed by Pd(PPh₃)₄ (1 equiv) and 1,3-dimethylbarbituric acid(30 equiv). The flask was sealed and shaken at rt for 1 day. Thereaction mixture was removed and the Lanterns were washed with DMF untilthe washings were clear (without any yellow color). Subsequently theLanterns were washed with the following solvents for 30 min intervals:3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of an aliquot cleavedfrom the lantern shows no remaining starting material. The Lanterns werethen dried on a lyophilizer overnight and carried on to the next step.

N-Capping/Aldehydes:

To a flask containing Lanterns was added DMF with 2% AcOH (0.800mL/Lantern) followed by 4-pyridinecarboxaldehyde (20 equiv). Thereaction mixture was shaken at rt for 1 hr then sodiumtriacetoxyborohydride (20 equiv) was added and shaking was continued.After 3 days the reaction mixture was removed and the Lanterns werewashed with the following solvents for 30 min intervals: DMF, 3:1THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of an aliquot cleaved fromthe lantern shows no remaining starting material.

Cleavage Protocol:

To a 96-well plate containing Lanterns was added a 15% solution ofHF/pyridine in stabilized THF (350 μL/Lantern). After 2 h the cleavagesolution was quenched with TMSOMe (700 μL/Lantern) and the contents ofeach well were transferred to a pre-weighed 2-mL vial. The Lanterns werewashed with an additional 200 μL of stabilized THF (or THF/MeOH) and thesolution was transferred to the 2-mL vial. The samples were concentratedon a GENEVAC® solvent evaporation system overnight without heating toafford the title compound1-(4-fluorophenyl)-3-((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-2-((methyl(pyridin-4-ylmethyl)amino)methyl)-6-oxo-2,3,4,5,6,7-hexahydrobenzo[h][1,5]oxazonin-9-yl)urea(7.5 mg, 84% yield). LCMS RT 0.69 min, observed [M+1]⁺ 549.28,calculated [M+1]⁺ 549.28). Loading masses for each alcohol wasdetermined on a FLEXIWEIGH® system.

Example 3: Synthesis of(4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-8-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine1,1-dioxide

Scaffold Loading:

To a flame-dried flask containing silicon-functionalized Lanterns wasadded a freshly prepared solution of TfOH in anhydrous DCM (9.0 equiv, 5g of TfOH/100 mL of DCM) was added. Each flask was shaken at RT for 10min at which time the Lanterns had turned bright orange. The deep redTfOH solution was removed via cannula and anhydrous 2,6-lutidine (12.0equiv relative to Si) was added. Once the Lantern color had changed fromorange to white,(9H-fluoren-9-yl)methyl(((4R,5R)-8-bromo-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)(methyl)carbamate,the scaffold (1.2 equiv. relative to Si) was added as a solution inanhydrous DCM (0.4 mL/Lantern) and the reaction mixture was shaken for48 h overnight. The loading mixture was removed and set aside (torecover any unreacted alcohol) and the Lanterns were washed with thefollowing solvents for 30 min intervals: DCM, THF, 3:1 THF/IPA, 3:1THF/H₂O, DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM. The Lanterns were thendried on a lyophilizer overnight and carried on to the next step.

Fmoc Removal:

To a flask containing Lanterns was added a solution of 20% piperidine inDMF (0.8 mL/Lantern). After shaking at rt for 30 min, the piperidinesolution was removed and the Lanterns were washed with the followingsolvents for 30 min intervals: DMF, 3:1 THF/H₂O, 3:1 THF/IPA, THF, DCM.QC analysis of an aliquot cleaved from the lantern shows no remainingstarting material. The Lanterns were then dried on a lyophilizerovernight and carried on to the next step.

N-Capping/Aldehydes:

To a flask containing Lanterns was added DMF with 2% AcOH (0.800mL/Lantern) followed by 4-pyridinecarboxaldehyde (20 equiv). Thereaction mixture was shaken at rt for 1 hr then sodiumtriacetoxyborohydride (20 equiv) was added and shaking was continued.After 3 days the reaction mixture was removed and the Lanterns werewashed with the following solvents for 30 min intervals: DMF, 3:1THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of an aliquot cleaved fromthe lantern shows no remaining starting material. The Lanterns were thendried on a lyophilizer overnight and carried on to the next step.

Cross-Coupling/Suzuki:

To each flask containing Lanterns was added ethanol (0.800 mL/Lantern)followed by phenylboronic acid (20 equiv), triethylamine (40 equiv) andPd(PPh₃)₂Cl₂ (1 equiv). The resulting mixture was degassed with a streamof N₂ before shaking at 60° C. After 4 days, the reaction mixture wasremoved and the Lanterns were washed with following solvents for 30 minintervals: DCM, DMF, NaCN solution (0.1M) in 1:1 THF/H₂O, DMF, 3:1THF/H₂O, 3:1 THF/IPA, THF, DCM. QC analysis of an aliquot cleaved fromthe lantern shows no remaining starting material.

Cleavage Protocol:

To a 96-well plate containing Lanterns was added a 15% solution ofHF/pyridine in stabilized THF (350 μL/Lantern). After 2 h the cleavagesolution was quenched with TMSOMe (700 μL/Lantern) and the contents ofeach well were transferred to a pre-weighed 2-mL vial. The Lanterns werewashed with an additional 200 μL of stabilized THF (or THF/MeOH) and thesolution was transferred to the 2-mL vial. The samples were concentratedon a GENEVAC® solvent evaporation system overnight without heating toafford the title compound(4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-8-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine1,1-dioxide (3.1 mg, 31% yield). LCMS RT 0.78 min, observed [M+1]⁺495.22, calculated [M+1]⁺ 495.22). Loading masses for each alcohol wasdetermined on a FLEXIWEIGH® system.

Compounds 1-53 were synthesized following similar procedure as above.The synthetic characterization data (LCMS) for Compounds 1-53 is givenin Table 2.

TABLE 2 Compound No. Observed [M + 1]⁺ Expected (M + H)⁺ 1. 485.23485.235 2. 549.28 549.275 3. 495.22 495.219 4. 553.26 553.261 5. 537.33537.332 6. 527.25 527.245 7. 559.23 559.225 8. 483.22 483.219 9. 509.23509.235 10. 485.23 485.235 11. 527.25 527.245 12. 499.25 499.25 13.485.23 485.235 14. 522.32 522.321 15. 551.34 551.336 16. 509.23 509.23517. 487.26 487.258 18. 568.26 568.261 19. 499.21 499.214 20. 527.25527.245 21. 527.25 527.245 22. 498.30 498.308 23. 610.44 610.203 24.562.51 562.303 25. 533.24 533.288 26. 524.3 524.324 27. 618.33 618.34128. 484.25 484.293 29. 566.45 566.253 30. 552.72 552.355 31. 532.26532.292 32. 582.56 582.308 33. 600.50 600.280 34. 576.53 576.282 35.551.53 551.298 36. 481.52 481.281 37. 518.52 518.277 38. 550.36 550.28339. 586.73 586.339 40. 557.48 557.288 41. 610.54 610.314 42. 615.59615.366 43. 572.50 572.287 44. 556.53 556.330 45. 572.50 572.301 46.539.40 539.335 47. 588.57 588.355 48. 527.31 527.335 49. 635.38 635.42950. 658.41 658.397 51. 695.49 695.403 52. 522.26 522.344 53. 672.49672.413

Example 4

A biochemical assay to identify small molecules that inhibit theneomorphic activity of purified IDH1-R132H was used to identifycompounds of interest. C-terminally His8-tagged IDH1-R132H protein wasexpressed in the E. coli Rosetta strain and purified by metal chelateaffinity chromatography. The ability of IDH1-R132H to convert α-KG to2-HG using NADPH is assayed by measuring consumption of NADPH in adiaphorase-coupled assay. Resazurin is a dark blue reagent that haslittle intrinsic fluorescence. In the presence of NADPH, Resazurin isreduced by diaphorase to resorufin, which is highly fluorescent with anexcitation peak at 579 nm and an emission peak at 584 nm (FIGS. 1A-G).

To validate the above assay, a set of compounds was screened in amulti-well format in duplicate. The average signal-to-background ratiowas about 10; the Z′ factor ranged from 0.7 to 0.85 and CV was <8% foreach of the four plates. The scale-up was facile and robust, with anaverage Z′ of about 0.74 for 101 plates, and yielding over hundred hitswith >=30% inhibition in both replicates. A more stringent cutoffof >=40% inhibition in both replicates, corresponding to >4 times thesum of the standard deviations of the negative and positive controls,yielded a smaller set.

To identify assay artifacts, such as compounds that activate diaphorasedirectly, another assay was developed as an alternative method tomeasure the activity of IDH1-R132H based on absorbance at 340 nm byNADPH (FIG. 2A-B). The assay solution contained 100 mM Tris.HCl pH 7.4,150 mM NaCl, 5 mM MnCl2, 0.03% BSA, 20 uM NADPH, 0.4 mM α-Ketoglutarateand 87 nM of recombinant IDH1-R132H. Absorbance is measured on aSpectraMax spectrophotometer (Molecular Devices) in kinetic mode.

Compound Selectivity Test: To define their selectivity, confirmedinhibitors of IDH1-R132H were tested in dose for their ability toinhibit: (i) wild-type IDH1, (ii) another α-Ketoglutarate-dependentenzyme, the histone demethylase GASC1, and, (iii) anotherNADP+-dependent dehydrogenase, G6PDH. Selectivity over the followingcriteria was studied:

(i) wild-type IDH1. The ability of the compound to inhibit IDH1-R132Hcompared to wild-type IDH1.

(ii, iii) Selectivity over GASC1 and G6PDH. Ideal compounds should notinhibit either GASC1 or G6PDH (IC50 difference >20-fold).

Step Description of Assay Conditions:

-   -   1. Dispense 5 μl of compounds to black 1536-well plates using        Echo liquid handling system.    -   2. Dispense 2.5 μl of assay buffer to positive control wells of        assay plates using Multidrop Combi dispenser.    -   3. Dispense 2.5 μl of enzyme mix to assay wells using Multidrop        Combi dispenser    -   4. Incubate at room temperature (about 20-25° C.) for 20 min.    -   5. Dispense 2.5 μl of substrate mix to initiate the reaction        using Multidrop Combi dispenser.    -   6. Incubate at room temperature for 50 min. Pre-read to identify        fluorescent compounds.    -   7. Dispense 2.5 μl of detection mix using Multidrop Combi        dispenser.    -   8. Incubate at room temperature for 30 min.    -   9. Read plates on Envision (Ex 535, Em 595).

The activity of Compounds to inhibit IDH1 (wild type) and IDH1-R132H isgiven in Table 3.

TABLE 3 IC₅₀ IDH1 IC₅₀ IDH1 Example No. (R132H) (Wild Type) GASC1 G6PDH1 I I ND IV 2 I IV IV IV 3 I IV IV IV 4 I IV ND IV 5 I IV ND IV 6 I IVND IV 7 I IV ND IV 8 I IV ND IV 9 I IV IV IV 10 I IV ND IV 11 III III IVND 12 II IV IV IV 13 III II ND IV 14 III IV IV IV 15 II III II IV 16 IIIII IV IV 17 III IV I IV 18 III III ND ND 19 II III ND ND 20 II IV IV IV21 III III IV IV 22 III IV ND IV 23 II ND ND 24 I ND ND 25 I ND ND 26 IND ND 27 I ND ND 28 III ND ND 29 II ND ND 30 I ND ND 31 I ND ND 32 IIIND ND 33 II ND ND 34 I ND ND 35 III ND ND 36 II ND ND 37 I ND ND 38 I NDND 39 I ND ND 40 III ND ND 41 II ND ND 42 II ND ND 43 II ND ND 44 II NDND 45 I ND ND 46 I ND ND 47 III ND ND 48 I ND ND 49 I ND ND 50 I ND ND51 I ND ND 52 II ND ND 53 I ND NDProtocol for the Synthesis of Example-52

Example-52

Step 1: Synthesis of b

Compound a was synthesized according to published procedure (Marcaurelleet al. J. Am. Chem. Soc. 2010, 132, 16962-16976). The remaining reagentsfor the following reaction are commercially available. To an oven-driedround-bottom flask equipped with a magnetic stirrer was added a (945 mg,2.61 mmol, 1.0 equiv) and 10 mL dichloromethane. PyBOP (1.50 g, 2.88mmol, 1.1 equiv) and diisopropyl ethylamine (1.01 g, 7.84 mmol, 3.0equiv) were added. The resulting mixture was cooled in an ice bathbefore isopropylamine (185 mg, 3.14 mmol, 1.2 equiv) was added as asolution in dichloromethane (3 mL) dropwise over 20 minutes. The mixturewas stirred for three days at room temperature. The reaction wasquenched with water and extracted with dichloromethane. The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated to yield a white solid. The soluble portions of the mixturewere taken up in diethyl ether and the insoluble phosphoramidebyproducts were removed via filtration. The solvent was removed in vacuoand the crude product was isolated. Flash chromatography on silica gel(0-50% Ethyl acetate in hexanes) gave the product (540 mg, 51%).

Step 2: Synthesis of c

To an oven-dried 2-necked round-bottom flask equipped with a magneticstirbar and condenser was added b (530 mg, 1.32 mmol, 1 equiv) in 15 mLtetrahydrofuran (final concentration 0.05 M). Borane-dimethylsulfidecomplex (500 mg, 5.68 mmol, 5.0 equiv) was added dropwise via syringeand the reaction was heated at 65° C. for 5 hr. The flask was placed onan ice bath and excess hydride was quenched by addition of methanoluntil bubbling stopped. The mixture was concentrated to an oil andevaporated three times with methanol to remove excess B(OMe)₃. The oilwas redissolved in a mixture of aqueous sodium potassium tartrate (10mL, 0.5 M) and methanol (10 mL) and the resulting slurry was heated atreflux (85° C.) for 12 hours to disrupt the boron-nitrogen complex.Volatiles were removed under reduced pressure and the resulting aqueousmixture was extracted with ethyl acetate. The combined organic extractswere washed once with brine, dried over magnesium sulfate, filtered, andconcentrated to provide the desired amine c as a colorless oil inquantitative crude yield (527.6 mg). The material was taken on withoutpurification.

Step 3: Synthesis of d

To a flame-dried round-bottom flask equipped with stirbar and purgedwith nitrogen was added c (427 mg, 1.10 mmol, 1.0 equiv) indichloromethane (final volume 15 mL, concentration 0.04 M). The solutioncooled in an ice bath and triethylamine (556 mg, 5.49 mmol, 5.0 equiv)and 2-fluoro-5-nitrophenylacetic acid chloride (598 mg, 2.75 mmol, 2.5equiv)(prepared as described in Marcuarelle et. al. J. Am. Chem. Soc.2010, 132, 16962-16976) were added via syringe. The reaction mixturetook on a dark red-orange color. The vessel was warmed to roomtemperature and allowed to stir overnight. The reaction was quenchedwith water and extracted with dichloromethane. The combined organicextracts were dried over magnesium sulfate and concentrated to yield thecrude product. The material was purified by flash chromatography onsilica gel (0-50% EtOAc in hexanes) to give the product d (526 mg, 84%).

Step 4: Synthesis of e

To a flame-dried 50 mL flask that had been purged with nitrogen wasadded ammonium fluoride (171 mg, 4.61 mmol, 5.0 equiv) followed by d(526 mg, 0.922 mmol, 1.0 equiv) in tetrahydrofuran (14 mL, finalconcentration 0.07 M) and tetrabutylammonium fluoride (1.21 g, 4.61mmol, 5.0 equiv). The mixture was stirred at room temperature overnight.The reaction was quenched with saturated aqueous ammonium chloride. Theorganic and aqueous layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith acetic acid solution (1.0 M in water) and brine and dried overmagnesium sulfate. The mixture was filtered and the filtrate wasconcentrated. Flash chromatography on silica gel (20-60% EtOAc inhexanes) yielded the deprotected alcohol (215 mg). This intermediate wasdissolved in THF (15 mL, final concentration 0.03 M) and placed in aflame-dried round-bottom flask with stirbar that had been purged withnitrogen. Sodium hydride (94 mg, 2.36 mmol, 5.0 equiv) was added in oneportion and the resulting mixture was allowed to stir overnight at roomtemperature. The reaction was quenched with not-quite-saturated aqueousammonium chloride solution. The organic and aqueous layers wereseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate andfiltered. The filtrate was concentrated to yield the crude product.Flash chromatography on silica gel (50-70% EtOAc in hexanes) affordedthe product as a white crystalline solid (122 mg, 30%).

¹H NMR (300 MHz, CDCl₃, 22° C.) δ 8.18 (d, J=3 Hz, 1H), 8.06 (dd, J=3, 9Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.56 (m, 1H), 4.13 (m, 1H), 3.64 (m, 2H),3.47 (m, 3H), 2.92 (s, 3H), 2.17 (m, 1H), 1.70 (m, 1H), 1.40 (s, 9H),1.22 (m, 6H), 0.98 (d, J=7 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃, 22° C.) δ162.8, 144.0, 131.4, 127.7, 123.9, 123.2, 80.2, 52.3, 51.5, 37.4, 36.2,28.3, 21.2, 19.8, 15.8.

Step 5: Synthesis of f

To a flame-dried flask equipped with a stirbar was added 10% palladiumon carbon (28.2 mg, 26 μmol, 0.1 equiv), followed by purging of theflask with nitrogen. e (115 mg, 256 μmol, 1.0 equiv) was added as asolution in ethanol (11 mL, final concentration 0.025 M). The mixturewas heated to 35° C. and a hydrogen atmosphere was applied via balloon.The reaction was allowed to progress for two hours, after which themixture was removed from heat and filtered through Celite and thesolvent was removed in vacuo to afford the crude product (95 mg, crudeyield 88%). The material was taken on crude.

Step 6: Synthesis of g

To a flame-dried 5 mL flask with stirbar that had been purged withnitrogen was added f (9.2 mg, 23 μmol, 1.0 equiv) and 500 μLdichloromethane. Cyclohexyl isocyanate (12.8 mg, 102 μmol, 4.5 equiv)was added and the mixture was stirred for four days. Extradichloromethane was periodically added to replace that which evaporatedover the course of the reaction. The reaction was quenched with waterand extracted with methylene chloride. The combined organic extractswere dried over sodium sulfate; the solution was decanted andconcentrated in vacuo to afford crude product. Flash chromatography onsilica gel (0-10% MeOH in dichloromethane) provided the product (10.4mg, 86%).

Step 7: Synthesis of h

To a small vial equipped with a stirbar was added g (10.4 mg, 20 μmol,1.0 equiv) in dichloromethane (600 μL, 0.02 M). Trifluoroacetic acid(444 mg, 3.89 mmol, 200 equiv) was added and the mixture was stirred for30 minutes. The mixture was then concentrated in vacuo and mixed withsaturated aqueous sodium bicarbonate. The resulting aqueous mixture wasextracted with dichloromethane; the combined organic extracts were driedover sodium sulfate. The solution was decanted and the solvent wasremoved by evaporation under a stream of dry nitrogen. The material wastaken on crude.

Step 8: Synthesis of Example-52

To a vial equipped with a stirbar was added 9 (9.6 mg, 22 μmol, 1.0equiv) dissolved in 2% acetic acid in dimethylformamide (612 μL, 0.036M). Isonicotinaldehyde (5.7 mg, 53 μmol, 2.4 equiv) was added viasyringe and the reaction was allowed to proceed for 90 minutes. Sodiumtriacetoxyborohydride (9.0 mg, 42 μmol, 1.9 equiv) was added and themixture was stirred for two days. The solvent was removed in vacuo at50° C. and the residue was taken up in saturated aqueous sodiumbicarbonate solution. The aqueous mixture was extracted withdichloromethane; the combined organic extracts were dried over sodiumsulfate. The solution was decanted and concentrated in vacuo. Theresidue was purified by high-pressure liquid chromatography to yield theproduct (4.9 mg, 42%).

¹H NMR (300 MHz, CDCl₃, 22° C.) δ 7.43 (m, 2H), 7.04 (m, 2H), 6.94 (m,1H), 5.45 (m, 1H), 4.78 (m, 1H), 4.17 (m, 1H), 3.75 (m, 1H), 3.51 (m,2H), 3.34 (m, 1H), 3.11 (m, 1H), 2.79 (m, 1H), 2.59 (m, 1H), 2.41 (m,1H), 2.22 (s, 3H), 1.88 (m, 5H), 1.56 (m, 6H), 1.23 (m, 6H), 0.94 (m,3H).

Synthesis of Example-50

Step 1 and 2—Reduction and N-Capping with Isocyanates

Lactam i (1 equiv.) and palladium (10% on activated carbon, 0.1 equiv.)were stirred in EtOH (25 mM) at 35° C. under a hydrogen atmosphere. Thereaction was monitored by LCMS for complete consumption of startingmaterial (1-2 h). The mixture was cooled, filtered through Celite andconcentrated to give the aniline derivative j.

The crude product was dried under vacuum and then dissolved in DCM (150mM) and transferred into a dried round-bottom flask flushed withnitrogen. Cyclohexyl isocyanate (1.5 equiv.) was added with a syringe.It was stirred overnight at room temperature. The mixture wasconcentrated and the product was isolated by column chromatography(DCM/MeOH gradient from 0 to 20% MeOH). Yield: 96%.

[α]_(D) ²⁰=−2.3° (c 1.0, CHCl3). IR (cm⁻¹)=3346, 2927, 2853, 2361, 2342,1692, 1611, 1551, 1497, 1451, 1393, 1365, 1249, 1217, 1149, 1086, 819.¹H NMR (300 MHz, CDCl₃-d) δ=7.34 (s, 1H), 7.24-7.16 (m, 3H), 6.86 (d,J=8 Hz, 2H), 6.67 (m, 1H), 5.52 (s, 1H), 4.44 (s, 2H), 4.15 (m, 1H),3.81-3.79 (m, 6H), 3.61-3.59 (m, 4H), 3.36-3.31 (m, 2H), 2.99-2.90 (m,3H), 2.61 (s, 3H), 2.09 (m, 1H), 1.90 (m, 2H), 1.69-1.55 (m, 4H), 1.43(s, 9H), 1.35 (d, J=7 Hz, 4H) 1.25 (s, 3H), 0.87-0.83 (m, 3H). ¹³C NMR(75 MHz, CDCl₃-d) δ=172.3, 159.5, 155.7, 152.5, 136.4, 130.7, 129.6,124.4, 123.02, 120.0, 114.1, 80.2, 77.6, 73.2, 72.8, 59.2, 55.6, 48.8,41.4, 38.0, 36.0, 34.1, 34.0, 30.0, 28.8, 26.1, 25.3, 25.2, 23.0, 15.4.HRMS (ESI) calcd for C₃₇H₅₄N₄O₇ [M+H]⁺: 667.3993. Found: 667.843.

Step 3—Boc Removal

2,6-Lutidine (1.26 mL, 10.8 mmol, 4 equiv.) and TBSOTf (1.86 mL, 8.1mmol, 3 equiv.) were added to a solution of j (1.8 g, 2.7 mmol, 1equiv.) in DCM (27 mL, 0.1 M) at room temperature and stirred overnight.The reaction was quenched with saturated NH₄Cl solution and extractedwith EtOAc. The combined organic extracts were dried over MgSO4,filtered, and concentrated to the crude silyl carbamate.

The resulting oil was dissolved in THF (22.5 mL, 1.2 M) and subsequentlyHF/pyridine (70% HF; 360 uL, 1 equiv. HF) was added. The mixture wasstirred for 30 min, quenched with saturated NH₄Cl and extracted withEtOAc. The combined organic extracts were dried over MgSO4, filtered,and concentrated. Product k was used without further purification.Yield: 98%.

[α]_(D) ²⁰=−25.7° (c 1.0, CHCl3). IR (cm⁻¹) 3342, 2927, 2853, 2361,1610, 1551, 1513, 1498, 1249, 1218, 1085, 1034, 820. ¹H NMR (300 MHz,CDCl₃-d) δ=7.55 (s, 1H), 7.26-7.24 (m, 3H), 6.87 (d, J=8 Hz, 2H) 6.44(m, 1H), 5.76 (m, 1H), 4.46 (s, 3H), 4.38 (m, 1H), 4.15 (d, J=14 Hz,1H), 3.86 (m, 5H), 3.59-3.30 (m, 4H), 3.09 (d, J=13 Hz, 1H), 2.81 (d,J=11 Hz, 1H), 2.58-2.35 (m, 6H), 1.91-1.54 (m, 6H), 1.34-0.84 (m, 10H).¹³C NMR (75 MHz, CDCl₃-d) δ=172.7, 159.5, 155.9, 151.4, 136.5, 130.8,130.0, 129.6, 125.0, 123.2, 119.7, 114.1, 89.0, 73.1, 72.7, 55.6, 54.0,51.9, 48.6, 37.6, 37.4, 34.1, 33.2, 30.0, 26.1, 25.3, 15.6. HRMS (ESI)calcd for C₃₂H₄₆N₄O₅ [M+H]⁺: 567.3468. Found: 567.4246.

Step 4—Reductive Amination

Starting material k (0.7 g, 1.24 mmol, 1 equiv.) was diluted in DMF(containing 2% Acetic acid; 88 mM). Isonicotinic aldehyd (0.128 mL, 1.36mmol, 1.1 equiv.) was added and the mixture was stirred for 1 h at roomtemperature. Subsequently sodium triacetoxyborohydride (340 mg, 1.61mmol, 1.3 equiv.) was added and the mixture was stirred for 3 days. Thesolvents were evaporated in vacuo and product Example-50 was purified bycolumn chromatography (DCM/MeOH gradient from 0 to 20% MeOH). Yield:93%.

[α]_(D) ²⁰=−6.2° (c 1.0, CHCl3). IR (cm⁻¹) 3349, 2929, 2852, 1604, 1551,1497, 1451, 1414, 1248, 1217, 1084, 820. ¹H NMR (300 MHz, CDCl₃-d)δ=8.51 (d, J=5 Hz, 2H), 7.53 (s, 1H), 7.22-7.14 (m, 4H), 6.85 (d, J=8Hz, 2H), 6.68 (dd, J₁=33 Hz, J₂=8 Hz, 2H), 5.69 (d, J=8 Hz, 1H),4.43-4.34 (m, 3H), 4.14 (d, J=13 Hz, 1H), 3.89-3.29 (m, 12H), 3.06 (d,J=11 Hz, 1H), 2.72 (d, J=13 Hz, 1H), 2.53 (d, J=13 Hz, 1H), 2.39 (m,1H), 2.19 (s, 3H), 1.90-1.53 (m, 6H), 1.33-0.88 (m, 10H). ¹³C NMR (75MHz, CDCl₃-d) δ=172.6, 159.5, 155.9, 151.8, 150.1, 149.0, 136.6, 130.7,130.0, 129.5, 124.6, 124.0, 123.6, 119.5, 114.2, 89.4, 73.1, 72.8, 62.6,59.2, 55.6, 53.3, 48.7, 44.2, 37.5, 34.6, 34.1, 26.1, 25.2, 15.9, 15.6.HRMS (ESI) calcd for C₃₈H₅₁N₅O₅ [M+H]⁺: 658.3890. Found: 658.3772.

To a solution of BRD5667 in DMF (10 mg in 0.372 mL, 50 mM) at roomtemperature was added sodium hydride (1.3 mg, 0.055 mmol). The mixturewas stirred for 10 minutes and 4-(2-chloroethyl)pyrrolidinehydrochloride (4.4 mg, 0.026 mmol) was added to the reaction mixture.The mixture was stirred at 40° C. for 24 h. Yield after HPLCpurification: 0.494 mg.

BRD5667 was distilled azeotropically three times with 20%dichloromethane in benzene and lyophilized overnight.

To a solution of BRD5667 in anhydrous tetrahydrofuran (83.3 mg in 3.87mL, 40 mM) under argon was added DBU (0.093 mL, 0.62 mmol) followed bydiphenyl phosphorazidate (0.1 mL, 0.465 mmol). The mixture was stirredfor 24 h. The solvent was removed under vacuum and the azide waspurified by column chromatography (0-20% MeOH in DCM). Yield afterpurification: 10 mg, 11%.

The azide (10 mg, 0.018 mmol) was diluted in tetrahydrofuran (0.35 mL,50 mM) in a dried LCMS vial. Triethylamine (10 uL, 0.07 mmol), thealkyne (7 uL, 0.05 mmol), and copper(I) iodide (0.34 mg, 0.0018 mmol)were added. It was stirred overnight at room temperature. Afterfiltration, the solvent was removed and the product was purified byHPLC. Yield after HPLC purification: 0.674 mg.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound of Formula (TB) or Formula (IC), or apharmaceutically acceptable salt thereof:

wherein: n is 0; q is 1; X₂ is —O— Cy1 is:

R₁ is C₁-C₆ alkyl; R₂ is:

R₁₂ is hydrogen, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, CONR₂₀R₂₁,C(O)R₂₀, or C(O)OR₂₁; R₁₃, R₁₄, and R₁₅ are each independently hydrogen;R₁₆ is hydrogen, halogen, aliphatic, substituted aliphatic, aryl,substituted aryl, heteroaryl or substituted heteroaryl; alternatively,when two of the R₁₃, R₁₄, R₁₅, and R₁₆ groups are attached to a carbonatom, together said two groups and said carbon atom may form a carbonylor an optionally substituted vinyl group; u is 1; w is 0, 1, 2, 3, 4, 5or 6; Cy3 is optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted heterocyclyl, optionallysubstituted aryl or optionally substituted heteroaryl; R₃ is selectedfrom:

each R₁₃′, R₁₄′ and R₁₅′ is independently hydrogen, C₁-C₆ alkyl, orsubstituted C₁-C₆ alkyl; each of R₁₆′ and R₁₇′ is independentlyhydrogen, C₁-C₆ alkyl, or substituted C₁-C₆ alkyl; R₁₁ is:

R₁₃″ is hydrogen, halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃,—C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy,alkylamino, substituted alkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic,substituted aliphatic, aryl or substituted aryl; R₄₀ is selected fromthe group consisting of:

and R₄₁ is hydrogen, halogen, aliphatic, substituted aliphatic, aryl,substituted aryl, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃,—C(O)R₂₀, —C(O)OR₂₀, —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy,alkylamino, substituted alkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl; q′ is 1; and R₂₀and R₂₁ are each independently hydrogen, halogen, aliphatic, substitutedaliphatic, aryl or substituted aryl.
 2. The compound of claim 1, whereinR₁ is methyl, ethyl or propyl.
 3. The compound of claim 2, wherein R₁ ismethyl.
 4. The compound of claim 1, wherein R₁₂ is C₁-C₆ alkyl orsubstituted C₁-C₆ alkyl.
 5. The compound of claim 1, wherein R₂ is:


6. The compound of claim 1, wherein R₃ is:


7. The compound of claim 6, wherein R₃ is


8. The compound of claim 1, wherein R₁₁ is a moiety selected from thoseshown in Table B: TABLE B


9. The compound of claim 1, wherein w is 0, 1 or
 2. 10. The compound ofclaim 1 selected from those shown in Table 1, or a pharmaceuticallyacceptable salt thereof: TABLE 1 1

(4R,5R)-8-(cyclopent-1-en-1-yl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 4

N-(((4R,5R)-8-(cyclohexylethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2- (pyridin-4-yl)acetamide 6

N-(((4R,5R)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 8

(4R,5R)-8-(cyclopropylethynyl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 10

(4S,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-3-ylmethyl)amino)methyl)-8- (pent-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 11

N-(((4R,5S)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide 13

(4S,5S)-8-(cyclopent-1-en-1-yl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-5-((methyl(pyridin-4-ylmethyl)amino)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocine 1,1-dioxide 18

4-(((((4R,5R)-8-(3-cyclopentylprop-1-yn-1-yl)-2-((R)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)(methyl)amino)methyl) benzoic acid

N-(((4R,5R)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-8-(3-methylbut-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methylnicotinamide 21

N-(((4S,5S)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-8-(4-methylpent-1-yn-1-yl)-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-N-methyl-2-(pyridin-3-yl)acetamide.


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 12. The compound of claim1, wherein the compound has the Formula (IC).
 13. The compound of claim1, wherein the compound has the Formula (TB).
 14. The compound of claim12, wherein R₃ is


15. The compound of claim 14, wherein R₁ is methyl.
 16. The compound ofclaim 13, wherein R₃ is


17. The compound of claim 16, wherein R₁ is methyl.
 18. The compound ofclaim 15, wherein R₂ is:


19. The compound of claim 18, wherein R₁₂ is CONR₂₀R₂₁, C(O)R₂₀, orC(O)OR₂₁.
 20. The compound of claim 19, wherein R₁₆ is C₁-C₆ alkyl. 21.The compound of claim 1, wherein R₁₂ is CONR₂₀R₂₁, C(O)R₂₀, or C(O)OR₂₁.22. The compound of claim 21, wherein R₁₆ is C₁-C₆ alkyl.
 23. Thecompound of claim 1, wherein R₁₃″ is aryl or substituted aryl.
 24. Thecompound of claim 23, wherein R₁₃″ is phenyl or substituted phenyl. 25.The compound of claim 17, wherein R₂ is:


26. The compound of claim 25, wherein w is
 1. 27. The compound of claim26, wherein R₁₂ is C₁-C₆ alkyl or substituted C₁-C₆ alkyl.
 28. Thecompound of claim 27, wherein Cy3 is an optionally substituted aryl oran optionally substituted heteroaryl.
 29. A method of ameliorating acell proliferative disease in a patient in need thereof comprising thestep of administering a compound according to claim 1 to said patient,wherein the cell proliferative disease is selected from glioma, acutemyeloid leukemia (AML), Burkitt's leukemia/lymphoma (B-ALL), melanoma,and prostate cancer.
 30. The method according to claim 29, wherein saidglioma is selected from astrocytomas, oligodendrogliomas, ependymomasand glioblastoma multiforme.